My long-term research strategy for a career as a translational physician-scientist is to: discover neuroendocrine and neuroimaging endophenotypes in postpartum depression (PPD), translate findings to develop methods to identify pregnant women at highest risk of developing PPD based on biological markers and develop gender-specific treatments targeted to underlying pathophysiology in women at high-risk of developing PPD. Depression is the leading cause of disease burden and years lost to disability for women in their childbearing years35. Women with a history of PPD, for unknown reasons, are at high risk of developing PPD with subsequent pregnancies 36-38. Suicide accounts for up to 20% of postpartum deaths39. Differential regulation of gonadal steroids, including neuroactive steroids (NAS), and ?-aminobutyric acid (GABA) during late pregnancy and the postpartum, via modulation of corticolimbic functional connectivity, may be involved in the pathophysiology of PPD. My pilot data prompted me to hypothesize that PPD is associated with: abnormal NAS and GABA regulation during pregnancy and abnormal postpartum cortical GABA and resting-state functional connectivity (rs-fc). No study has prospectively investigated the effect of perinatal gonadal steroids on GABA and resting-state functional connectivity in PPD. My research findings will fill this knowledge gap and will advance scientific knowledge of biomarker identification in gonadal steroid-modulated mood disorders. To my knowledge, it is the first combined GABA MRS/resting-state functional connectivity MRI study in PPD and the first to investigate the role of sex steroids in resting-state functional connectivity (rs-fc) in PD. Specific Aim 1: To measure plasma NAS and GABA in late pregnancy and in the postpartum in those at low-risk (LR) and high-risk (HR) for PPD. Specific Aim 2: To measure cortical GABA/Creatine with magnetic resonance spectroscopy in the anterior cingulate cortex (ACC) and corticolimbic rs-fc in HR depressed and LR non- depressed postpartum women using the ACC as a seed area. I hypothesize that: abnormalities in the biosynthetic/metabolic pathway of progesterone, evidenced by altered NAS levels during pregnancy will be associated with decreased GABA levels during pregnancy and in the postpartum in the HR cohort; decreased plasma GABA levels in HR cohort both during pregnancy and the postpartum will be associated with PPD; PPD is associated with decreased cortical GABA in the ACC and decreased ACC rs-fc with limbic areas. Further hypotheses are discussed in the proposed research plan. The NIMH K23 is the bridge (i.e. pathway for training and mentorship) for this early stage investigator to develop into an independently-funded physician- scientist. The K23 will advance my knowledge of reproductive endocrinology with an emphasis on developing novel investigative techniques and train me in neuroimaging to investigate the interactions of the reproductive endocrine system on neural circuitry in depression so to elucidate the pathophysiology of depression during times of reproductive flux with the goal of developing gender-specific treatments in women.